Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 16
EEG Traits
Timothy A. Pedley
Introduction
At the most fundamental level, cortical excitability and electrical organization are genetically specified, and it is probable that each identifiable electroencephalographic (EEG) pattern is a heritable trait or made up of a combination of heritable traits. As yet, no specific genetic locus has been identified in humans as controlling any spontaneous brain rhythm, whether normal or abnormal, although this will likely one day be possible. A spontaneous, synchronized EEG pattern has been discovered in the mocha mice mutant that is regulated by a single recessive locus.89 In addition, a defect in a single genetic locus can result in generalized spike-and-wave activity in mutant mice, and a number of independent loci have been identified that give rise to phenotypically similar spike-and-wave patterns, but each of these is associated with different abnormalities of cellular excitability13,88 (see also Chapter 37). In terms of epilepsy, it is now clear that rare epileptic syndromes that aggregate in families result from definable monogenic abnormalities (see Chapters 15 and 18). It is also evident, however, that seizure susceptibility reflects complex alterations in multiple factors governing neuronal excitability. At the present time, recording the EEG is the only readily available method for detecting an abnormal seizure tendency in asymptomatic individuals, or for classifying the physiologic basis of persons with seizures or epilepsy. Electroencephalography has accordingly assumed major importance in the genetic analysis of epilepsy.
Genetic Studies of Electroencephalographic Patterns
Normal Electroencephalographic Activity
The role of genetic factors has interested investigators from the beginning of scientific study of EEG phenomena. A variety of evidence supports substantial genetic influence on patterns of cerebral electrical activity, although results of many studies cannot be accepted uncritically. Davis and Davis20 first pointed out similarities in the EEGs of eight pairs of identical twins, and their observations were corroborated by Loomis et al.75 and by Raney.93 Lennox et al.70,71 studied nonepileptic identical and fraternal twins. Electroencephalograms from monozygotic twins were judged to be identical in 85% of twin pairs, whereas EEGs from nonidentical twins were viewed as different 95% of the time. Later quantitative studies of alpha frequency, voltage and phase relations, and sleep patterns have consistently identified EEGs as concordant from identical but not from nonidentical twins.59,113 Differences between EEG recordings from a pair of monozygotic twins are no greater than the variations that occur spontaneously in sequential recordings from the same individual. Rates of EEG maturation, the appearance and disappearance of age-specific patterns, and, in older subjects, age-related slow activity are all virtually identical in monozygotic twins.101,114,115 Lykken et al.76 studied frequency spectra in twins and found them to be the same in 96% of monozygotic pairs. Butler et al.12 related asymmetries in alpha rhythm to hereditary factors. Vogel et al. have also reported that other patterns aggregate in families, suggesting a genetic basis. These include low-voltage EEG background activity in children,115 variants of the alpha rhythm,116 and some types of beta activity.112,117 The evidence in support of these last examples is not entirely convincing because of the lack of adequate controls for state of alertness, details about drug effects, and the possible influence of anxiety or stress related to the recording methods and circumstances. However, Kubicki67 has also reported that the presence of rhythmic posterior beta activity is under genetic control, and Koshino and Isaki66 demonstrated familial occurrence of the mu rhythm. Although different modes of inheritance have been proposed for some of these patterns, none can yet be accepted as proved. A low-voltage alpha EEG pattern is a genetic trait that has been associated with psychiatric disorders, most notably anxiety disorders and alcohol use.40,41 There is some evidence that this trait is linked to the same region of chromosome 20q as panic disorder. Alpha rhythm traits have not been associated with epilepsy. Ellingson et al.39 studied the occurrence of 14/s and 6/s positive spike bursts in the EEGs of twins and triplets and concluded that this was genetically determined. However, similar rates for 14/s and 6/s positive spike bursts have been reported in the EEGs of unselected and unrelated children.74
Nonspecific Abnormal Electroencephalographic Patterns
Kuhlo et al.68 more fully characterized a rare pattern of 4- to 5-Hz rhythmic activity over the posterior head regions of young adults; this had been described earlier by Vogel et al.116 Once present, this finding persisted in serial EEGs. Kuhlo et al.68 concluded that the pattern was genetically determined, because it occurred identically in two monozygotic twin pairs and in 10% of siblings of affected probands.
Doose et al.27,29 have described “abnormal theta rhythms” in young children, which they correlated with increased susceptibility to febrile seizures and generalized idiopathic epilepsy. The pattern is mainly one of 4- to 6-Hz rhythmic activity, maximal over the parietal areas, and is more common in boys than girls. The finding was strongly age dependent and occurred in about 30% of siblings at ages 3 to 4 years. More recently, Baier and Doose4 have demonstrated an increased risk for generalized epileptiform activity in the EEGs of siblings if probands show abnormal theta rhythms. In the authors’ laboratory, it has sometimes been difficult to distinguish this pattern unequivocally from rhythmic slow activity occurring normally during drowsiness or as part of nonspecifically abnormal generalized slowing of background activity. Another age-dependent finding is 2- to 4-Hz rhythmic activity over the occipital and posterior head regions.46 The genetic features of this, however, are even
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less clear. First, rhythmic occipital delta waves occurred as often in siblings of controls as in siblings of delta-positive probands. Second, in younger children (ages 3 to 4 years), occipital delta rhythms were more common in the siblings of controls than in siblings of probands, but the reverse was true in older children (ages 5 to 10 years). Third, delta rhythms did not correlate with epileptiform activity, but their occurrence with generalized epileptiform activity reduced the frequency with which generalized spike-and-wave activity or photoparoxysmal responses were identified in siblings.
FIGURE 1. Prevalence of generalized spike-and-wave activity in normal children. (Data from Gerken H, Doose H. On the genetics of EEG anomalies in childhood. III. Spikes and waves. Neuropädiatrie. 1973;4:88–97 [Table III]; and Eeg-Olofsson O. The development of the electroencephalogram in normal children and adolescents from the age of 16 through 21 years. Neuropädiatrie. 1971;3:11–45. [Fig. 10]; graphs kindly prepared by Dr. W. A. Hauser.)
Epileptiform Activity
Generalized Spike-and-Wave Activity
Generalized spike-and-wave (GSW) activity is a genetically determined epileptiform pattern that aggregates in families. Lennox70 first proposed that GSW discharges were the manifestation of a genetic trait, and the now classic studies of the Metrakoses et al.81,82,83,84 unambiguously established the familial occurrence of GSW activity. About 35% of siblings and about 10% of parents of probands with GSW discharges show a similar (but not necessarily identical) epileptiform abnormality in their EEGs.83 Metrakos and Metrakos83 concluded that GSW activity was caused by an autosomal dominant gene with age-dependent penetrance. In the general population, GSW discharges have been reported in the waking EEGs of 0.3% to 1.8% of all children,14,37,38,47 but the finding is age dependent and peak prevalence is 2.8% in children 7 to 8 years old (Fig. 1). If EEGs include sleep, GSW activity can be demonstrated in 15% of normal 3- to 4-year-old Swedish children (7.9% of Swedish children of all ages)38 and in 16.8% of normal 3-year-old Japanese children.106,107 Studies of GSW activity in siblings and offspring are complicated by the presence of epilepsy in most probands. That the two may not be invariably linked is clear from the studies of Metrakos and Metrakos,82,84 who showed that the EEG spike-and-wave trait can be dissociated from clinical seizures. Thus, it is possible that the rates of GSW activity reported in relatives are confounded by the presence of epilepsy, and presumably the type of epilepsy, in the proband. Nonetheless, it is unarguable that a substantial percentage of siblings of children with epilepsy and GSW activity will also exhibit the spike-and-wave trait. Figures range from 7% to 17%,24,47 but as in population studies, rates are age dependent and, perhaps additionally, related to the subtype of idiopathic epilepsy. Thus, 13% of siblings of all probands have GSW activity between the ages of 3 and 6 years.47 In probands with “generalized minor seizures,” the figure increases to 34% in siblings between the ages of 2 and 3 years.25 In children of parents with idiopathic generalized epilepsy, 19% manifest GSW activity in their EEGs,6 and multiple spike-and-wave (“polyspike”) activity occurs in 15% of family members with myoclonic seizures.109 Degen and Degen21 have reported that 72% of siblings of patients with absence epilepsy and nearly 50% of siblings of probands with febrile seizures have EEGs showing generalized 2.5- to 4-Hz spike-and-wave activity, but these data cannot be accepted without further confirmation. The exact mode of inheritance of the GSW EEG trait remains uncertain, and both autosomal dominant and polygenic modes of inheritance have been proposed.
A susceptibility gene at the EJM1 locus on chromosome 6 is involved in the juvenile myoclonic epilepsy phenotype in some families.51 The same gene also seems to influence expression of the EEG abnormality in juvenile myoclonic epilepsy.36,50
GSW discharges most likely involve epileptogenic alterations in thalamocortical circuitry that have been implicated in absence seizures based on studies of spontaneously occurring homozygous mouse mutants11 (Chapter 37), the WAG/Rij rat model of absence epilepsy,80 and supporting clinical data. The three key elements in the circuit are believed to be thalamic relay neurons, thalamic reticular neurons, and cortical pyramidal neurons.15 Abnormalities in this thalamocortical system predispose to absence seizures and characteristic EEG discharges,100 although details remain incomplete. A contributing abnormality appears to be mutations in one of the genes (CACNA1H) that encode the T-type calcium channels that control phasic activation of cortical pyramidal neurons.16,65 Physiologic studies of several of the mutations have demonstrated functional changes in channel behavior that would favor epileptogenic firing patterns.65 Point mutations in the CACNA1A gene, which encodes a Cav2.1 P/Q-type calcium channel, have been implicated in a family in which absence epilepsy is inherited through several generations in an autosomal dominant pattern.57 Several affected family members also have cerebellar ataxia. In all individuals with both ataxia and absence seizures, there was a point mutation in the CACNA1A gene, which encodes the main subunit of Cav2.1 channels. In one asymptomatic family member with typical 3-Hz spike-and-wave discharges, however, the mutation was absent. γ-Aminobutyric acid (GABA)B mechanisms have also been implicated in absence seizures and generalized spike-and-wave discharges.12 Thus, while
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thalamocortical circuits, calcium channel mutations, and GABAergic inhibition all seem to be involved in the absence epilepsy phenotype—and probably other idiopathic generalized epilepsy phenotypes as well—details of how individual components of these phenotypes, including differences in the pattern of generalized spike-and-wave activity, remain unclear. Recent studies of genetic absence rats from Strasbourg (GAERS) using genomewide scans indicate polygenic control of specific spike-and-wave discharge variables.96
FIGURE 2. Prevalence of photoparoxysmal responses in normal children. (Graphs kindly prepared by Dr. W. A. Hauser and derived from combined data of Doose H, Gerken H. On the genetics of EEG anomalies in childhood IV. Photoconvulsive reaction. Neuropädiatrie. 1973;4:162–171; and Eeg-Olofsson O. The development of the electroencephalogram in normal children and adolescents from the age of 16 through 21 years. Neuropädiatrie. 1971;3:11–45. [Figs. 7 and 8].)
Photoparoxysmal Responses
Photosensitivity—that is, the development of generalized bursts of irregular spike, multiple spike, and spike-and-wave activity in response to intermittent unpatterned light stimulation—is a familial trait, as first pointed out by Nekhorocheff86 and then studied more completely by Daly and Bickford,17 Davidson and Watson,19 Watson and Davidson,120 Daly et al.,18 Schaper,99 and Watson and Marcus.121 Despite differences in definitions of photosensitivity, criteria for terming a response photoparoxysmal, and recording methods, these early studies found that photoparoxysmal responses occurred in about 20% to 60% of near relatives of probands. Later studies have found somewhat lower rates. Doose and Gerken26 and Doose et al.31,33 compared EEG findings in siblings of children who had photoparoxysmal responses with those of nonepileptic controls. Overall, a photoparoxysmal response could be recorded in about 16% of siblings, but rates were strongly age dependent (Fig. 2). Thus, photoparoxysmal responses to rhythmic light flashes were rare below age 4 but were seen in 32% of siblings ages 11 to 12 years, and abnormal photic responses were more common in girls than in boys. Photoparoxysmal responses occurred in about 5% of control children. Electroencephalographic photosensitivity could be demonstrated in 10% to 20% of siblings of children with epilepsy but without photoparoxysmal responses. The presence of GSW activity in the EEGs of probands did not increase the chance of photoparoxysmal responses occurring in siblings, and photoparoxysmal responses without other EEG abnormalities did not increase seizure risk in siblings. Thus, GSW activity and photoparoxysmal responses appear to be genetically independent phenomena. More recently, Waltz and Stephani118 also studied photoparoxysmal responses in the siblings of patients with epilepsy. The occurrence of photoparoxysmal responses was age dependent with maximum rates seen between 5 and 15 years of age. If one parent was photosensitive, about 39% of all siblings were also photosensitive. However, in siblings between 5 and 15 years of age, the rate was 50%. When a proband was photosensitive but neither parent was, 14% of siblings demonstrated photosensitivity. Sisters were somewhat more likely to be photosensitive than their brothers.
Photoparoxysmal responses are a feature of the idiopathic generalized epilepsies. They are found in 13% to 18% of patients with absence epilepsy and in 30% to 35% of patients with juvenile myoclonic epilepsy.52 Tauer et al.102 performed genomewide linkage scans to identify susceptibility loci for photosensitivity and to determine the genetic relationship with idiopathic generalized epilepsy. Families were studied in which at least two siblings had photoparoxysmal responses. For the analysis, the families were divided into two groups. In one, affected family members had predominantly photoparoxysmal responses or photic-induced seizures (PPR families). The other group included families with photoparoxysmal responses and either unprovoked spontaneous GSW discharges or unprovoked idiopathic generalized seizures (PPR/IGE families). In the PPR families, there was a significant association with chromosomal region 6p21.2. In the PPR/IGE families, there was linkage to chromosomal region on 13q31.3. Based on additional analyses, the authors concluded that the locus on 13q31.3 contributes to an epileptogenic mechanism that is shared by both the photoparoxysmal responses and idiopathic generalized epilepsy. The locus on 6p21.2 appears to predispose to photosensitivity itself. That photoparoxysmal responses are genetically heterogeneous is supported by an earlier report of 16 families with juvenile myoclonic epilepsy.91 In this study, genomewide scans showed significant linkage to chromosomes 7q32 and 16p13. These findings suggest that different genetic loci for photosensitivity contribute to the different idiopathic generalized epilepsy phenotypes.
Focal Epileptiform Activity
The central-midtemporal sharp wave discharge is associated with idiopathic localization-related epilepsy in children (benign focal epilepsy of childhood with central-midtemporal sharp waves; “benign rolandic epilepsy”) but often occurs as an asymptomatic expression of a genetic trait. Central-midtemporal sharp waves occur in about 35% of siblings and in about 3% to 20% of parents of probands with this EEG finding.9,22,55 The discharges have generally been considered to be highly concordant in twins, but recent data suggest that the genetic influence on benign rolandic epilepsy is much less than previously thought.108a In some reports, up to 66% of probands28 and nearly 15% of siblings and parent10,95 have
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had bilateral EEG abnormalities that included GSW activity and bursts of intermittent rhythmic delta waves. In other studies, however, transmission of central-midtemporal spikes has not correlated with other genetic EEG patterns.35,47 Focal spikes, mainly of the central-midtemporal variety, can be detected in about 1% to 3% of normal children in population studies.14,35,38 Both autosomal dominan9,55 and polygenic21 modes of inheritance have been postulated to account for the familial occurrence of the central-midtemporal spike trait, but there has been considerable variability in study design and often failure to separate asymptomatic individuals with EEG abnormalities only from those with the characteristic EEG discharge and benign rolandic epilepsy.
Doose et al.28 found that only 22% of 147 children with central-midtemporal sharp waves had benign rolandic epilepsy. Other children with central-midtemporal sharp waves had neonatal seizures, febrile seizures, generalized tonic–clonic seizures, or other focal seizures that were not typical of rolandic epilepsy. In an analysis of 18 twin pairs, with at least one twin having typical benign rolandic epilepsy, Vadlamudi et al.110 were unable to demonstrate concordance for classic rolandic epilepsy, although all twins had seizures. They concluded that the mode of inheritance of benign rolandic epilepsy (not just central-midtemporal sharp waves) is much more complex than has been thought, and that noninherited factors are likely to be of importance.
Degen et al.23 recorded waking and sleep EEGs in patients with complex partial seizures. The study included 19 patients and 29 siblings. Seven asymptomatic siblings (24%) showed epileptiform activity, and seven of the patients (37%) had at least one sibling with an epileptiform EEG.
Gibbs et al.48,49 were the first to observe occipital sharp waves that disappeared with age in children without seizures. Gastaut44 drew attention to “benign partial epilepsy with occipital spike waves,” although Camfield et al.13 had earlier described four similar cases as a form of migraine. Today, two forms of benign childhood occipital epilepsy are recognized: An early-onset form (Panayiotopoulos type; see Chapter 237) and a late-onset form (Gastaut type; see Chapter 238). The interictal features of the two syndromes are identical. Occipital sharp waves are found in about 0.6% of normal children between 1 and 16 years of age.14,38 The highest peak is in younger children: 0.9% of children ages 2 to 4 years will have occipital sharp waves.14 As with central-midtemporal sharp waves, the prevalence of occipital sharp waves in normal children decreases with age: Only about 0.1% after the age of 6 years.14,90 In one large EEG laboratory, occipital sharp waves occurred in 10.7% of children referred for a variety of reasons.60 Genetic aspects of occipital sharp waves and benign occipital epilepsy have been less well studied than central-midtemporal sharp waves and benign rolandic epilepsy. While Gastaut and Zifkin reported that 36% of affected children had a family history of epilepsy,45 children with benign occipital seizures do not usually have a family history of similar seizures. Ferrie et al.42 analyzed 113 patients with early-onset benign occipital epilepsy. Febrile seizures occurred in 15%, and there was a history of epilepsy in 7% of first-degree relatives. Other EEG abnormalities occurred in 25% of the patients and included central-midtemporal sharp waves, frontal sharp waves, and generalized discharges. A few families with several affected children have been reported in somewhat more detail. Kuzniecky and Rosenblatt69 described a family in which three of four children had symptoms consistent with late-onset benign occipital epilepsy. The fourth asymptomatic child had occipital sharp waves on EEG. Occipital sharp waves were also found in 26% of other asymptomatic younger family members. In the family described by Nagendran et al.,85 two children had occipital sharp waves. One of these had visual hallucinations followed by drowsiness; the other had visual hallucinations and two generalized convulsions. Two children were asymptomatic, but the EEG in one showed central-midtemporal sharp waves and occipital slowing in the other. Doose et al.32 studied 19 patients with occipital sharp waves. Seizures consistent with early-onset benign occipital epilepsy occurred in 7 (37%); only five of these had occipital sharp wave foci. Occipital foci were found in 43% of 21 relatives. Only 1 of 11 relatives of probands with benign occipital epilepsy also had occipital seizures. Children with occipital seizures also had febrile seizures (one relative), benign rolandic seizures (one relative), and generalized tonic–clonic seizures (six relatives).
Limitations in Using the EEG for Genetic Studies
Although EEG has been, and continues to be, a major tool in genetic studies of epilepsy, several factors limit its utility or at least require careful consideration in study design and data analysis. These include maturational, biologic, and interpretive issues.
Maturational Issues
Virtually all studies of genetic EEG patterns show age dependence. Thus, prevalence figures derived without taking age into account will be inaccurate or even misleading.
All EEG activity in the first decade of life and during much of the second reflects maturational processes taking place within the central nervous system, and some of these are gender related.7 Although these maturational processes cannot yet be specified in detail for any EEG phenomenon, they presumably are determined by genetically controlled changes in neuronal cell types, numbers, and connectivity; neurotransmitters and receptors; synaptic interactions; myelination; and circuitry. In general, the younger the child, the more pronounced are EEG differences between any two points in time. In premature infants, for example, substantial changes in EEG activity may normally occur at intervals of 1 to 2 weeks. On the other hand, the EEG in a normal 6-year-old child is not very different from that of an 8-year-old, but both can be distinguished from the EEG of a healthy young adult. Acquired brain insults and abnormal genetic influences are superimposed on this normal developmental substrate. Thus, clinical and EEG findings are always the result of complex interactions between normal maturational events and the modifying effects of acquired or adverse genetic factors. It may well be that the expression and character of certain EEG patterns depends on critical interactions occurring within a fairly narrow time window. It is therefore not surprising that age histograms differ for various epileptiform patterns60,61 (Fig. 3). Furthermore, it is not known how or in what ways genetic control of cerebral excitability and electrical organization is altered in the presence of an abnormal substrate, for example, one injured by hypoxia or intracerebral hemorrhage.
Biologic Issues
Variability of Electroencephalographic Findings
Electroencephalographic activity in the healthy adult is normally very stable over considerably long periods of time.8,79,105,109,111 Almost nothing, however, is known of the stability of epileptiform patterns, especially in terms of the morphologic and other distinguishing features that form the basis for most interpretations and classifications.
It is well accepted that sleep affects the morphology of generalized epileptiform discharges. This is most readily seen
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with classic 3-Hz spike-and-wave activity, in which the well-formed spike-and-wave paroxysms seen with the patient awake give way during sleep to discharges of shorter duration, composed of spikes and multiple spikes that recur in a fragmentary way, either with or without a consistent slow-wave component.87,98,99 It is possible to demonstrate similar although often less dramatic effects of sleep on other types of generalized epileptiform activity as well. To the extent that morphology is used to classify patients with similar seizures or syndromes, awareness of the effect of state is important.
FIGURE 3. Age histograms of various epileptiform patterns in children. (Reproduced from Kellaway P. Maturational and biorhythmic changes in the electroencephalogram. In: Anderson VE, Hauser WA, Penry JK, et al., eds. Genetic Basis of the Epilepsies. New York: Raven Press; 1982:21–33.)
FIGURE 4. Different patterns of generalized spike-and-wave activity.
FIGURE 5. Examples of normal drowsy patterns in children. A: Continuous generalized rhythmic theta activity. B: Paroxysmal bursts of bisynchronous rhythmic delta activity.
In generalized-onset seizures, interictal EEGs show bilateral, symmetric, synchronous spikes with spike-and-wave and multiple spike-and-wave discharges. Beyond this generic description, however, considerable variability exists in details of how the epileptiform activity is expressed (Fig. 4). Patients with mainly generalized tonic–clonic seizures, for example,
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most commonly demonstrate “atypical” spike-and-wave activity, consisting of bursts of spikes and irregularly repeating 4- to 6-Hz spike-and-wave complexes. Sometimes, however, such patients also show 3-Hz spike-and-wave paroxysms or bursts of multiple spike-and-wave activity. In childhood absence seizures, the EEG most commonly reveals classic 3-Hz spike-and-wave activity, but close inspection reveals that the initial frequency is often 4 Hz and that the terminal frequency, especially in paroxysms lasting 10 seconds or longer, is usually 2 to 2.5 Hz. Some children with clinically typical childhood absence seizures show quite irregular spike-and-wave discharges,72 and this does not appear to affect the character or prognosis of the disorder.73 In relatives of children with absence seizures, even greater variability is seen in the expression of the spike-and-wave trait. In juvenile myoclonic epilepsy, multiple spike-and-wave activity is considered to be the characteristic—even pathognomonic—interictal EEG finding. Although this pattern may be the most specific, it occurs in fewer than half the patients clinically classified as having the disorder.58,108 Other common epileptiform abnormalities in single EEGs of patients with juvenile myoclonic epilepsy include 3-Hz spike-and-wave activity and “atypical” 4- to 6-Hz spikes and spike-and-wave activity. No systematic study of the variability in patterns of epileptiform activity over time in individual patients has been performed. In all syndromes of idiopathic generalized epilepsy, almost all variations of GSW activity can be seen, although one or another pattern may statistically predominate in some seizure types.119 Thus, it is probably not biologically meaningful or even accurate to use frequency or morphologic details of GSW activity as major criteria for narrowly defined epileptic phenotypes. It may, however, be reasonable to attempt to study the genetics of different EEG patterns alone. This issue is of considerable importance as molecular biologists are transforming our understanding of epilepsy by identifying chromosomal loci and specific genes associated with different types of epilepsy. The clinician plays a pivotal role in linkage
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studies by providing precise and useful definitions of the condition under study. What role EEG and other features should play in defining epileptic syndromes and how elastic or inflexible these definitions should be are important issues for the genetic study of epilepsy (as well as for classification schemes). Some critical discriminating factors are already evident, as in the need to separate photoparoxysmal responses from spontaneous or hyperventilation-induced GSW activity. Another important issue is the dissociation that can occur between EEG findings and clinical manifestations. Genetic EEG traits can be expressed in asymptomatic individuals in the population at large as well as in families with both clinically affected and unaffected members. More than one heritable EEG pattern may be seen in individuals with a “classical” clinical phenotype (e.g., central-midtemporal spikes or generalized spike-and-wave discharges in patients with benign occipital epilepsy). Genetic studies that use EEG need to recognize this variability in their design. At present, no single electrical event is unique to a particular form of epilepsy or epileptic syndrome.
Timing of Electroencephalographic Recordings
Kellaway et al.64 have demonstrated that the occurrence in the EEG of GSW activity shows consistent time distributions that reflect modulation by interactive but independent circadian and ultradian processes. Similar biorhythmic modulation may affect the ability to record focal spikes as well.63 From a practical standpoint, sleep and sleep deprivation will increase the yield of “positive” EEGs. Timing of EEG samples, therefore, may be a critical factor in genetic studies. A related problem is that of sampling. Longer EEGs and EEGs recorded on more than one occasion increase the chance of demonstrating a specific epileptiform abnormality. In patients with probable epilepsy, about 29% to 50% will have epileptiform abnormalities on the first EEG, but if multiple EEGs are obtained, the yield increases to 59% to 92%.77,97
The Issue of Epileptogenicity
Epileptiform patterns are a reliable signature of an individual’s susceptibility to seizures, but they do not quantify the magnitude of this risk. In other words, there is a strong but by no means absolute correlation between seizures and interictal epileptiform discharges. This consideration has implications for using EEG data to estimate seizure risk (see further on). Behavioral and EEG expressions of epilepsy appear to be under at least partially separate genetic control, and development of recurrent seizures best fits a multifactorial model involving both genetic and environmental factors.1 Thus, prevalence studies in relatives of probands with epilepsy always show higher rates for EEG abnormalities than for seizures.1 It is clear that the various epileptiform patterns differ in their degree of epileptogenicity. For example, among children referred to an EEG laboratory for various reasons, including known or possible epilepsy, only about 40% of those with central-midtemporal spikes had seizures.60,61 In the same cohort, on the other hand, seizures occurred in about 90% of children with other temporal spike foci and in about 75% of those with frontal or multifocal spikes. Of children with generalized epileptiform discharges, about 70% with “atypical” 4- to 6-Hz spike-and-wave activity and nearly 100% with 3-Hz spike-and-wave activity had seizures. With rare exceptions, however, there is at present no reliable way to relate quantitatively any interictal measure of epileptiform activity to clinical seizures.103 Frost et al.43 provided preliminary evidence of computer-derived parameters of interictal spike waveforms that showed promise in assessing seizure risk.
FIGURE 6. Age histograms of continuous (A) and paroxysmal (B) drowsy patterns in children. Paroxysmal bursts of rhythmic delta activity often normally contain sharply contoured or spikelike components (lower dotted sections in B). (Reproduced from Kellaway P. An orderly approach to visual analysis: characteristics of the normal EEG of adults and children. In: Daly DD, Pedley TA, eds. Current Practice of Clinical Electroencephalography. 2nd ed. New York: Raven Press; 1990:139–199, with permission.)
FIGURE 7. Age histograms of “lesional” and “benign” central spike foci in children. (Reproduced from Kellaway P. Maturational and biorhythmic changes in the electroencephalogram. In: Anderson VE, Hauser WA, Penry JK, et al., eds. Genetic Basis of the Epilepsies. New York: Raven Press; 1982:21–33, with permission.)
Interpretive Issues
Interpretation of the biologic significance of EEG findings by the electroencephalographer can play an important role in genetic studies. At the simplest level is the electroencephalographer’s concept of “normal” or “abnormal” and view of deviations from normative data (to the extent these exist). What are the limits of normal biologic variability, and when do deviations reflect abnormal brain function? A related issue is the identification of patterns considered epileptogenic. The electroencephalographic literature is an embarrassing repository of confused, ill-considered, and unsupported opinions regarding the epileptic significance of various EEG patterns. Although most electroencephalographers no longer consider 14/s and 6/s positive spike bursts, wicket spikes, rhythmic temporal theta
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bursts of drowsiness (psychomotor variant), or small sharp spikes as anything other than benign variants having no association with seizures, other problems remain. Not all sharply contoured transients or paroxysmal discharges are epileptiform, and not all epileptiform patterns are epileptogenic. Some discrepancies in prevalence figures undoubtedly relate to more or less liberal criteria for considering a discharge epileptiform. Thus, Metrakos and Metrakos81 reported that GSW activity occurred in 10% of their control subjects, whereas Doose et al.30,34 and Andermann and Straszak2 found GSW discharges in fewer than 2% of controls. Paroxysmal delta activity occurring normally during drowsiness in children is an especially vexing problem, because these hypnagogic bursts often contain sharp or spikelike components62 (Fig. 5). To the eye of this author, for instance, FIGURE 1 of Doose and Gundel27 does not show “abortive bilateral synchronous spikes and waves” but rather illustrates a nonspecific burst of rhythmic delta waves during drowsiness, probably a normal phenomenon. Furthermore, drowsy patterns in children may be either continuous or paroxysmal, and this characteristic is age elated62 (Fig. 6). Another seemingly unsolvable problem is that of the 6-Hz spike-and-wave discharge. When this takes the “phantom” form described by Marshall,78 most electroencephalographers consider it of no consequence. When the discharge is of higher voltage and maximal frontally, however, considerable controversy exists regarding its clinical significance. Some investigators deny that it has any relation to epilepsy,104 whereas others consider it a variation of GSW activity.56 It is even sometimes difficult to tell from a single EEG if the epileptiform activity is focal or generalized. In many patients with GSW activity, for example, the paroxysmal discharge occasionally appears in a limited or incomplete form. Such fragments of an otherwise typical generalized abnormality then appear as “focal” spikes, especially over the frontal or frontal-central regions. Conversely, some epileptogenic foci, most often those involving mesial parasagittal areas, give rise in scalp EEG recordings to bilateral discharges (“secondary bilateral synchrony”), which can be misinterpreted as generalized spike-and-wave activity. Especially if epileptiform activity is not abundant, a single EEG sample may not be sufficient to characterize the discharge unequivocally as focal or generalized. Accurate discrimination among different types of unambiguous spike discharge is also necessary. Thus, not all spikes occurring in the central and midtemporal areas are “benign” (Fig. 7). Finally, there is considerable variability in EEG interpretation, including recognition of artifact, among different observers,92 and this variability is influenced in part by specific reader characteristics.122
Role of Electroencephalogram in Estimating Risk for Seizures in Siblings and Offspring
Despite the limitations already described, knowledge of the proband’s EEG is of some help in estimating the risk for epilepsy in siblings. Although data from siblings are frequently used to estimate risk for offspring, the two groups are not, of course, genetically comparable. Epidemiologic studies suggest that risk for epilepsy in offspring is similar to that reported for siblings.53 However, it is not possible to determine in what way EEG findings modify this risk. This is because data are either unavailable or derived from sample sizes too small to provide reliable risk estimates.
In siblings of probands with epilepsy and GSW activity, risk for seizures or epilepsy does not appear to be increased above that conveyed by the proband’s epilepsy alone.3,53 Similarly, if the proband has epilepsy and a photoparoxysmal response that is not accompanied by spontaneous or hyperventilation-activated GSW activity, sibling risk for seizures is not increased above that related to the proband’s epilepsy alone.3,31,54 However, if the proband’s EEG contains both GSW discharges and a photoparoxysmal response, risk for epilepsy in siblings more than doubles.54 Thus, the genetic effects of GSW activity and photoparoxysmal responses seem to be additive.
Summary and Conclusions
The EEG is an important tool for identifying individuals with increased susceptibility to seizures, including carriers of genetic traits. Evidence is growing that specific EEG patterns are under
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complex and heterogeneous genetic control, and animal studies indicate that similar EEG patterns may arise from different and independent genetic mechanisms. Although the EEG has been and will continue to be an important phenotypic determinant in genetic studies of epilepsy, its use is limited by maturational, biologic, and interpretive considerations. Used with caution, the EEG can be helpful in estimating the risk for seizures in siblings and offspring of probands with epilepsy.
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